Lecture 12: Coronaviruses & COVID-19

SARS-CoV-2 Virology

Positive sense, ssRNA virus with one segment, thus NOT subject to reassortment

Coronaviruses undergo high rates of recombination when RdRp detaches from one template and resumes elongation on another

Lipid enveloped derived from a host cell harbors the viral spike protein

Receptor binding domain (RBD) mediates binding to host cell angiotensin-converting enzyme (ACE2), which serves as a cellular receptor for viral entry

Antigenic drift has focused on the RBD of spike, producing viral variants given Greek letter names

No evidence of change in virulence

SARS-CoV-2 incubation period

Median incubation time is 4-5 days from exposure to symptom onset

Transmission can occur pre-symptomatically (48 hrs) or asymptomatically (never develop symptoms)

SARS-CoV-2 Pathogenesis

Viral dsRNA is sensed by PRRs, triggering type I IFN production

Type I IFN is critical for controlling early viral replication and triggering adaptive immunity

Subset of patients fail to control viral replication and secrete high levels of pro-inflammatory cytokines (TNF, IL-1, IL-8, and IL-6)

Inflammatory mediators such as IL-6 stimulate C-reactive protein (CRP) from hepatocytes

CRP levels predict disease severity

Serum levels of pro-inflammatory cytokines at hospitalization predict patient survival

Risk factors

Male sex, increased age, and pre-existing medical co-morbidities (e.g. obesity, hypertension)

COVID-19 Symptoms

Common: fever, myalgia, headache, nasal congestion, sneezing, cough, sore throat, GI symptoms (Nausea, diarrhea)

More specific: anosmia (loss of smell), dysgeusia (altered taste)

Pneumonia is the most frequent serious manifestation

Complications include acute respiratory distress syndrome, hyper-coagulability (thromboembolic complications including DVT, PE, stroke), myocardial injury, neurologic sequelae, shock, organ failure, death

COVID-19 Generalized Clinical Course

Week 1: Non-specific flu-like illness:

Fever

Cough

Anosmia and/or ageusia

Week 2: Subset of patients, oxygen saturation drops, and respiratory rate increases, Immune dysregulation

Week 3-4: Thromboembolic complications and bacterial infections

Paxlovid

Oral combination of nirmatrelvir and ritonavir (NIR/RIT) to treat mild-to-moderate COVID-19

Nirmatrelvir inhibits the viral 3CL protease, so that active, smaller viral proteins cannot be produced from precursor polyprotein

Reduction in progression to hospitalization or death if given within 3 days to high-risk patients

VEKLURY (remdesivir)

Delivered intravenously

Nucleoside analog competes with one of the normal building blocks of RNA, ATP, thus inhibiting viral RNA replication

Molnupiravir

Delivered orally

Causes mutations in the newly synthesized viral RNA strand, ultimately shutting down viral replication

Dexamethasone

Lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone

Baricitinib

Inhibitor of Janus kinase, blocking JAK1 & 2

Tocilizumab

Anti–IL-6 receptor mAb

Comirnaty, Pfizer, SpikeVax, Moderna

mRNA-based vaccines containing mRNA encoding for pre-fusion stabilized Spike surrounded by a lipid nanoparticle

≥6 months old

NUVAXOVID, Novavax

Protein Subunit vaccine contain pre-fusion spike protein and an adjuvant

≥12 years old

COVID-19 Active Vaccines Contraindications

History of a severe allergic reaction after a previous dose or to a component of the COVID-19 vaccine

History of a diagnosed allergy to a component of the COVID-19 vaccine

Safe in immunocompromised individuals but efficacy may be compromised

Vaccine risk of myocarditis is 7X lower than infection risk and decreases with longer dosing intervals